Identification of a pyridine derivative inducing senescence in ovarian cancer cell lines via P21 activation
Identification of a pyridine derivative inducing senescence in ovarian cancer cell lines via P21 activation
复制标题
DOI：
10.1111/1440-1681.12891
复制
发表时间：
2018-05
影响因子：
2.9
通讯作者：
D. Shang;Yanfang Wu;Ya Ding;Ziwen Lu;Yanting Shen;F. Zhu;Hanqing Liu;Chunyin Zhu;Z. Tu
中科院分区：
文献类型：
--
作者：
D. Shang;Yanfang Wu;Ya Ding;Ziwen Lu;Yanting Shen;F. Zhu;Hanqing Liu;Chunyin Zhu;Z. Tu
细胞衰老是一种不可逆的细胞生长停滞状态。越来越多的证据表明细胞衰老有助于体内肿瘤抑制。然而，只有少数抗癌药物被发现会诱导细胞衰老。寻找能够通过诱导衰老来抑制癌细胞生长的新化合物正在成为最有吸引力的研究领域之一。为了测试候选化合物对癌细胞生长的影响，进行了细胞增殖测定、衰老相关 β-半乳糖苷酶 (SA-β-gal) 染色和流式细胞术测定。利用免疫荧光、蛋白质印迹和qRT-PCR实验进一步研究候选化合物的分子机制。我们证明，来自 46 种化合物的吡啶衍生物 4-(4-氟苯基)-2-苯基-5,6,7,8-四氢喹啉 (FPTHQ) 可以以剂量依赖性方式诱导卵巢癌细胞衰老。 FPTHQ 通过诱导 A2780 细胞 G0/G1 细胞周期停滞来抑制生长。在 FPTHQ 处理的 A2780、OVCAR-3 和 SKOV-3 细胞系中观察到 SA-β-gal 活性增加。此外，FPTHQ处理增加了A2780细胞中MMP3的蛋白水平以及IL-6和IL-8的mRNA水平，表明细胞中出现了衰老相关的秘书表型（SASP）。此外，我们发现在 FPTHQ 处理的卵巢癌细胞中 p21 上调并且 DNA 损伤积累。到目前为止，我们的数据表明，FPTHQ 可以通过引起过度的 DNA 损伤来激活 p21 信号通路，从而诱导多种卵巢癌细胞系衰老。
Cellular senescence is a state of irreversible cell growth arrest. Increasing evidence suggests that cellular senescence contribute to tumour suppression in vivo. However, only a few anti‐cancer drugs have been discovered to induce cellular senescence. Searching for new compounds which can inhibit cancer cell growth by inducing senescence is becoming one of the most attractive research fields. To test the effects of candidate compounds on cancer cell growth, cell proliferation assays, senescence‐associated β‐galactosidase (SA‐β‐gal) staining, and flow cytometry assay were performed. Immunofluorescence, western blot, and qRT‐PCR experiments were used to further study the molecular mechanisms of the candidate compounds. We demonstrated that a pyridine derivative, 4‐(4‐fluorophenyl)‐2‐phenyl‐5, 6, 7, 8‐tetrahydroquinoline (FPTHQ), from a pool of 46 compounds can induce senescence of ovarian cancer cells in a dose‐dependent manner. FPTHQ caused growth inhibition by inducing G0/G1 cell cycle arrest in A2780 cells. Increased activities of SA‐β‐gal were observed in FPTHQ‐treated A2780, OVCAR‐3 and SKOV‐3 cell lines. In addition, FPTHQ treatment increased the protein levels of MMP3 and the mRNA levels of IL‐6 and IL‐8 in A2780 cells, indicating the appearance of senescence‐associated secretary phenotype (SASP) in the cells. Furthermore, we found that p21 was up‐regulated and DNA damage was accumulated in FPTHQ‐treated ovarian cancer cells. So far, our data suggest that FPTHQ can induce senescence in multiple ovarian cancer cell lines through activation of p21 signalling pathway by causing excessive DNA damage.